Pharmacological Reports
2006, 58, suppl., 153–164
ISSN 1734-1140
Copyright © 2006
by Institute of Pharmacology
Polish Academy of Sciences
Review
Pulmonary endothelium in the perinatal period
Sheila G. Haworth
Vascular Biology & Pharmacology Unit, Institute of Child Health, 30 Guilford Street London WC1N 1EH
Correspondence: Sheila G.Haworth, e-mail: [email protected]
Abstract:
The pulmonary circulation is the only system in the body which does not have a dress rehearsal in utero. The pulmonary endothelium
plays a pivotal role in ensuring that the resistance falls rapidly after birth so that the lungs can receive and process the entire cardiac
output for the first time. It transduces signals triggered by environmental changes to the underlying smooth muscle cells, controlling
their reactivity and regulating pulmonary vascular tone. It also clears alveolar fluid. This review addresses the mechanisms involved
in these processes and considers failure of adaptation, the syndrome of Persistent Pulmonary Hypertension.
Key words:
pulmonary endothelium, nitric oxide, prostacyclin, endothelin-1, adaptation, pulmonary hypertension, perinatal life
Abbreviations: ADMA – asymmetric dimethylarginine,
cAMP – cyclic AMP, cGMP – cyclic GMP, COX – cyclooxygenases, DDAH – dimethylarginine dimethylaminohydrolase,
ET-1 – endothelin-1, ETA – endothelin-1 receptor type A, ETB
– endothelin-1 receptor type B, iNOS – inducible nitric oxide
synthase, L-NAME – N/-nitro-L-arginine, nNOS – neuronal
nitric oxide synthase, NO – nitric oxide, PDE phosphodiesterase, PGI – prostacyclin, PPHN pulmonary hypertension of
the newborn, PVR – pulmonary vascular resistance, VEGF –
vascular endothelial growth factor, VPF – vascular permeability factor, VSMC – vascular smooth muscle cell
Introduction
The pulmonary endothelium plays a crucial role in adaptation to extra-uterine life. Its two most important
functions are to help reduce pulmonary vascular resistance in order to permit the entire cardiac output to
pass through the lungs for the first time and to facilitate the clearance of alveolar fluid. In response to
changes in environmental factors such as oxygen ten-
sion, blood flow, endothelial stretch, circulating cytokines and growth factors, the endothelium synthesizes
and/or extracts many vaso-active mediators. These include
nitric oxide (NO), prostacyclin (PGI2), endothelin-1, norepinephrine, angiotensin-1 and thromboxane. The endothelium transduces signals triggered by environmental
changes to the underlying smooth muscle cells, controlling their reactivity and regulating pulmonary vascular tone. The endothelial layer also acts as a barrier,
regulating exchange of fluids and nutrients between the
blood and surrounding tissue. This review summarises
some of the more important aspects of endothelial
function in perinatal life.
1. Fetal life
During fetal life the endothelial cells are squat, have
a narrow base on the subendothelium and a low surface: volume ratio, with considerable overlap of latPharmacological Reports, 2006, 57, suppl., 153–164
153
eral cell borders [49, 52]. The arterial lumen is small,
offering a high resistance to flow. Pulmonary vascular
resistance (PVR) is probably kept high during fetal
life due to a significant release of vasoconstrictor substances including endothelin-1(ET-1) and leukotrienes
and low basal release of vasodilators such as NO and
PGI2 in the presence of a low oxygen tension [3, 60,
61]. A mechanically-induced increase in pulmonary
blood flow or exposure to vasodilators such as
a raised oxygen tension, PGI2 and acetylcholine only
induces transient vasodilatation [2, 4].
2. Normal Adaptation to extra-uterine life
Endothelial permeability
During fetal life the lung is filled with fluid produced
by the alveolar epithelium [102]. The liquid is absorbed by the alveolar epithelium at birth [5,16]. The
pulmonary capillary endothelium is more permeable
in newborns than adults [90]. Fetal pulmonary endothelial intercellular junctions are complex and fenestrated while they are tighter and less complex in older
babies, indicative of improved barrier function. The
higher endothelial permeability in fetal pulmonary
vessels is probably due to the combined actions of hypoxia, a high level of circulating ET-1, vascular endothelial growth factor (VEGF) and angiotensin II. ET-1
induces endothelial permeability [108] and ET-1 receptor antagonists can prevent capillary leakage [30].
VEGF, originally identified as vascular permeability
factor (VPF), is a potent inducer of plasma extravasation [35, 36] and its production is high during fetal development [48]. Angiotensin II may affect endothelial
permeability via the release of prostaglandins and
VEGF [130]. By contrast, an increase in NO has been
shown to prevent endothelial leakage in the lung
[119]. The postnatal increase in NO and the simultaneous reduction in endothelin may contribute to tightening of endothelial junctions after birth. More recent
studies on the newborn lung have demonstrated the
important role of the Rho GTPases in maintaining endothelial junctional integrity, emphasising the necessity of sustaining a high Rac1 to RhoA ratio [143].
The scaffolding proteins in the endothelial cell
membrane may also change at birth and contribute to
the perinatal changes in endothelial barrier function.
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Pharmacological Reports, 2006, 57, suppl., 153–164
PECAM-1 (CD31) influences transendothelial migration of inflammatory cells, mechanosignal transduction and angiogenesis [27, 59, 127]. Considerable
PECAM-1/CD31 is expressed on fetal rat endothelial
junctions and expression decreases after birth when
the blood-gas barrier is formed [82]. Caveolin-1 is
a component of caveolae, an endothelial scaffolding
protein [69] which regulates the assembly of different
signalling molecules at the plasma membrane (lipid
rafts) [92]. Studies on caveolin-1 (–/–) mice indicate
that caveolin-1 plays a dual regulatory role in controlling lung microvascular permeability, acting as
a structural protein required for caveolae formation
and caveolar transcytosis and as a tonic inhibitor of
eNOS activity to negatively regulate paracellular permeability [118].
Endothelial leakage occurs in pulmonary hypertension, irrespective of aetiology. NO inhalation may
prevent pulmonary edema both by improving endothelial barrier function and enhancing vascular relaxation [17, 42]. Overexpression of angiotensin-1 produces leakage-resistant vessels and angiotensin-1 is
protective in vitro [12, 40]. Potential therapeutic approaches include inhibition of VEGF, RhoA and other
molecules [135, 136, 144]. The natural mediator
sphingosine 1-phosphate (S1-P) activates Rac1 and
has considerable therapeutic potential [43].
Ensuring the postnatal fall in PVR
The transition to air breathing stimulates several
physiological actions including drainage of fetal lung
fluid, rhythmic distension of the lung, and an increase
in oxygen tension all of which contribute to the fall in
PVR [1, 71, 73, 107]. The pioneering studies of Dr.
Dawes and his colleagues in Oxford in the 1960s on
fetal sheep showed that mechanical ventilation reduced PVR, and that the response was enhanced when
the inspired gas was enriched with oxygen [28]. Forty
years later, no single factor has yet been identified as
being primarily responsible for the initiation of vasodilatation at birth. Nor do we know whether the endothelial cell or the smooth muscle cell is the prime target. It is probable that the abrupt expansion of the
lungs leads to a cascade of events which facilitate the
activation of vasodilator responses and reduce vasoconstrictor stimuli from the endothelium. The onset of
breathing is associated with an increase in circulating
bradykinin and the release of PGI2 and NO [23, 64,
126], thought to be caused by the sudden increase in
The pulmonary endothelium in the perinatal period
Sheila G. Haworth
pulmonary blood flow imposing a sheer stress on the
endothelium to promote their release. Although the
NO pathway appears to play a crucial role in regulating the vasoreactivity of the transitional circulation it
is not essential since endothelial NOS (eNOS) deficient mice survive and there is no evidence that either
inducible NOS (iNOS) or neuronal NOS (nNOS)
compensates for the absence of eNOS [89]. Irrespective of the signalling pathway under consideration, it
is generally assumed that the pulmonary arteries are
solely responsible for the postnatal fall in PVR. This
is unlikely because the pulmonary veins are not passive conduits. Newborn porcine pulmonary veins respond to acetylcholine to a greater extent than pulmonary arteries [8].
Functional studies usually acknowledge inhomogeneity between endothelial cells of conduit and peripheral vessels, but this is crude oversimplification. It is
well established that endothelial cell populations of
the mature pulmonary circulation are heterogeneous,
differences exist between cells from large and small
vessels, arteries and veins and between cells within
the same vascular region [29, 146]. Heterogeneity is
evident even before birth. During embryonic development the endothelial cells show high plasticity and
undergo constant changes in protein expression profile to match the requirements of the developing vessel [44, 97, 104, 109]. Endothelial hererogeneity is
demonstrated in the newborn pulmonary circulation
by the response to bradykinin. In newborn piglets bradykinin- induced relaxation of isolated conduit pulmonary arteries is dependant on prostaglandin and
NO, dependence on NO increasing with age. By contrast, bradykinin-induced relaxation of isolated resistance arteries is solely dependant on NO at birth, to be
largely replaced by a hyperpolarising factor generated
through an SKF525a-sensitive pathway [19]. The
regulation of these alternative signal transduction
pathways in the immature normal and hypertensive
pulmonary vasculature has still to be determined.
Role of specific mediators
Nitric oxide: All three NOS isoforms have been
identified in the fetal lung [68, 122]. NO production is
regulated by transcription, post-transcriptional modification, substrate availability, intracellular localization, superoxide production and co-factor availability
[47]. Endothelial release is influenced by a variety of
factors, including shear stress, O2 tension, and growth
factors.
The basal release of NO helps control resistance in
the ovine fetal and transitional circulation [37]. The
pulmonary arterial pressure in fetal and newborn
lambs was increased by infusion of Nw -nitrol-arginine (L-NAME). At birth, basal NO release is
low in isolated porcine intrapulmonary arteries and
increases significantly during the first week of life.
Newborn isolated ovine and porcine conduit arterial
and fetal and newborn porcine resistance arteries fail
to relax to acetylcholine, the response maturing during the first two weeks of life [2, 18, 79, 133]. By contrast, isolated fetal and newborn porcine pulmonary
veins relax well in response to acetylcholine at birth,
although like the arteries, the response improves with
age [8]. Significant release of NO has also been demonstrated in newborn ovine pulmonary veins [41],
possibly helping explain the ovine in vivo response to
L-NAME noted above. A relatively poor receptor mediated response is perhaps not surprising, given the
marked changes occurring in the endothelial cell
membrane as the surface/ volume ratio increases at
birth. Muscarinic receptor density increases rapidly
immediately after birth and the subtypes change [53].
But the relatively poor newborn relaxant response is
not restricted to receptor dependant mechanisms because the vessels do not relax to the calcium ionophore A23187 [79, 133]. Nor is the relatively poor endothelial dependant relaxation at birth due to the pulmonary arterial SMCs being incapable of relaxation.
The vessels relax in response to exogenous NO although this response also improves significantly during the first 2–3 weeks of life [79, 133]. There is no
lack of NOS at birth [54]. Endothelial NOS (eNOS)
protein and gene expression increase markedly towards term, and increase further to reach a maximum
at 2–3 days of life [54, 66]. But the activity of NOS in
crude porcine lung homogenates is low in the near
term foetus, higher when measured 5 min after birth
and peaks at 3 days [9]. Activity is always greater in
the particulate than the soluble fraction, and is almost
entirely calcium dependant at all ages. Thus as in the
adult, the predominant NOS enzyme at birth is the
constitutive eNOS isoform.
There is no absolute or relative deficiency of the
NOS co-factor BH4 [100]. The efficacy of NOS can
be reduced by the action of endogenous inhibitors,
primarily asymmetric dimethylarginine which competes with the NO substrate L-arginine (ADMA)
Pharmacological Reports, 2006, 57, suppl., 153–164
155
[134]. This could explain the low level of eNOS activity in fetal life. ADMA levels are high in amniotic
fluid and increase towards term and levels are also
high in fetal blood. ADMA would be expected to exert a significant tonic inhibitory effect on NOS at such
concentrations. ADMA is present in the urine of
healthy newborn infants, and gradually declines to become undetectable by 5 days of age [106]. ADMA is
metabolised to citrulline by the dimethylarginine dimethylaminohydrolase enzymes, DDAH I and II,
both of which are highly expressed in the fetal lung.
Each isoform is developmentally regulated and
DDAH II activity increases rapidly immediately after
birth [10, 80]. ADMA and DDAH could play a significant role in the regulation of the fetal and newborn
pulmonary vasculature.
The pulmonary arterial SMC being targeted by the
endothelium derived vasoactive substances is itself
changing rapidly. Basal accumulation of cGMP is
high at birth but falls rapidly to a lower adult level by
three days of age [133]. This postnatal fall in cGMP
might be explained by the high expression of phosphodiesterase (PDE)5 mRNA and hydrolytic activity
found in the newborn rat lung [114]. Studies on lungs
of several species also showed that PDE5 was responsible for a greater proportion of PDE activity during
the first week of life than in the adult [95, 114]. Despite the basal accumulation and enhanced accumulation of cGMP in response to NO and NO donors, the
relaxation response of newborn vessels is less than
might be expected. This might be accounted for by
the smooth muscle cell membrane being more depolarised at birth than later [33].
Prostacyclin (PGI2): Arachidonic acid metabolism within endothelial cells leads to the production of
vasoactive eicosanoids: prostaglandins or leukotrienes. The circulating concentration of vasoconstrictor
leukotrienes C4 and D4 decreases at birth [129] and
that of endothelial-derived PGI2 increases, facilitating
SMC relaxation [13, 70, 123, 124].
PGI2, is produced mainly by the endothelium [20].
It is a powerful vasodilator of both systemic and pulmonary vascular beds [93] and vasodilates the fetal
pulmonary circulation [24, 25]. PGI2 is produced by
the cyclooxygenases COX-1 and COX-2 [76]. Arachidonic acid, first liberated from phospholipid pools
by phospholipase A2, is converted to PGH2 by COX
and PGH2 is converted to PGI2 by the action of PGI2
synthase [137]. The PGI2 receptor belongs to the family of G-protein coupled receptors [50, 99]. Its effects
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Pharmacological Reports, 2006, 57, suppl., 153–164
are mediated by cAMP, though there may also be
a cAMP-independent coupling of the PGI2 receptor to
the activation of K+ channels that is important in the
relaxation of SMCs [138]. The levels of PGI2 during
early fetal life are low and this effect may be attributed to the inhibitory action of plasma glucocorticoids
on endothelial COX-1 gene transcription and COX
expression via a glucocorticoid receptor [63]. PGI2
levels increase at birth, a change coinciding with increasing fetal plasma estrogen levels in sheep, guinea
pigs and also in humans [7, 46, 110, 125]. Physiologic
levels of estradiol 17-(E2) induce COX-1 gene expression [62] and activate synthesis of PGI2 in ovine
fetal pulmonary artery endothelial cells [125].
Birth is thought to be associated with the release of
bradykinin, leading to the release of PGI2. Whether or
not PGI2 is crucial to the postnatal reduction in pulmonary arterial pressure is still uncertain. PGI2 synthase expression is low at birth in the media of porcine pulmonary arteries and increases rapidly in the
first week of life. In ovine pulmonary artery segments, PGI2 synthesis was considerably higher in
newborn than fetal vessels [124]. The increase occurred in the endothelial and SMCs of both intact vessels and cultured cells, and was caused by upregulation of COX-1 activity, related to a maturational
increase in COX-1 gene expression. COX-2 protein
was not detected.
The sudden increase in shear stress at birth and the
fall in PVR coincides with the increased release of
NO and PGI2 [1, 73], suggesting that the two agents
may act in concert to effect the vasodilatory action of
shear stress. An abrupt increase in flow stimulates the
release of both NO and PGI2 in cultured endothelial
cells [6, 21, 31, 132]. Recent studies in chronically
prepared fetal lambs indicate that NO-cGMP cascade
is a more potent modulator of pulmonary vascular
tone during acute haemodynamic stress than prostaglandins and that NO may mediate PGI2-induced pulmonary vasodilation [149]. NOS inhibition completely blocked shear stress-induced pulmonary vasodilatation, whereas COX inhibition had no effect. In
addition, NOS inhibition attenuated PGI2-induced pulmonary vasodilation, indicating that PGI2 acts largely
by NO release [149]. Although NO inhibitors block
vasodilatation resulting from increased oxygen and
rhythmic lung distension, COX inhibitors attenuate
vasodilatation caused by rhythmic distension [139].
Apart from inhibiting VSMC contractility, PGI2
also inhibits VSMC growth in vitro [75, 105]. The ef-
The pulmonary endothelium in the perinatal period
Sheila G. Haworth
fects of PGI2 on VSMC growth have also shown to be
site-specific as PGI2 inhibited proliferation of human
SMCs from distal pulmonary arteries, but not from
proximal pulmonary arteries [142].
Endothelin: The level of circulating ET-1 is high
in the normal term foetus and falls rapidly during the
first week of life. Endothelial release of this potent
vasoconstrictor [148] is stimulated by hypoxia, the
mechanical stimulation of shear stress and stretch,
and chemical stimuli such as thrombin, norepinephrine, transforming growth factor-b, phorbol esters and
calcium ionophores. ET-1 is the major isopeptide produced by endothelial cells but two other endothelin
isopeptides have been described, ET-2 and ET-3.
ETA receptors have a high affinity for ET-1 and
ET-2 and are found mainly on SMCs and mediate
vasoconstriction in most vascular beds [58]. ETB receptors have affinity for all endothelins. Vasoconstrictor (ETB) receptors are present on vascular SMCs and
vasodilator ETB receptors are found on endothelial
cells and mediate vasodilatation via release of NO,
PGI2 or via ATP-gated K+ channels [39, 81, 150]. In
the presence of a high vascular tone ET-1 has a vasodilatory effect but similar infusions have a vasoconstrictor effect when pulmonary vascular tone is decreased during acute ventilation [22]. ET-1generally
causes transient vasodilatation followed by sustained
vasoconstriction. Studies in newborn piglets have
shown that ET-1 is abundant in the lung parenchyma
and pulmonary arteries at birth [74]. Its expression
decreases at 2 days and increases again at 10 days but
at a lower level than in the newborn [74]. ETA and
ETB receptor binding sites are densely distributed
over the smooth muscle cells of pulmonary vessels,
with a relative increase in ET-B with age. Between
birth and three days vasodilator ETB receptors are
transiently expressed on the pulmonary arterial endothelial cells [56] and the vasodilator response to ET-1
increases after birth in both pulmonary arteries and
veins [117].
Angiotensin: The role of angiotensin in the regulation of the perinatal circulation is not understood.
Angiotensin II is an octapeptide formed from decapeptide angiotensin I by angiotensin-converting enzyme and is a powerful vasoconstrictor of pulmonary
vascular SMCs. It is first expressed on the endothelium of large proximal pulmonary arteries in the pseudoglandular stage of lung development and extends
distally during gestation [97]. In the rat lung expression of angiotensin-converting enzyme is 10 times
lower at birth than in the mature animal [97, 141]. The
vasoconstricting effects of angiotensin are largely due
to angiotensin-mediated increases in the production of
ET-1 [57, 94], suggesting that angiotensin release may
decrease immediately after birth.
3. Failure to adapt to extra-uterine life:
PPHN
Failure of the pulmonary circulation to adapt normally to extrauterine life causes persistent pulmonary
hypertension of the newborn (PPHN). The pulmonary
arteries fail to remodel after birth and the vessels remain thick-walled [51]. This condition has a high
morbidity and mortality rate of 10–20%, despite the
advent of inhaled NO therapy. It can be idiopathic but
is more usually associated with hypoxia secondary to
abnormalities of lung development or infection. It is
also a feature of certain types of congenital heart disease. Thus PPHN is multifactorial in origin but the
nature of the underlying defect causing failure to
adapt to extrauterine life is uncertain. It has been
shown to involve failure of endothelium-dependent
and/or independent relaxation, a primary structural
abnormality of the target SMCs and an excess of endothelin, and possible of other vasoconstrictor agonists such as thromboxane or an isoprostane.
Hypoxia is a common cause of PPHN in babies. In
vitro hypoxia alters endothelial metabolism of vasoactive agents, such as eNOS, 5-hydroxytryptamine, and
angiotensin-converting enzymes [14, 85, 98, 112]. It
also increases endothelial permeability which facilitates leakage of growth factors and blood cells into
the underlying SMC layer [143, 147].
Role of specific mediators
Nitric oxide: Neonatal pulmonary hypertension affects both the release of, and response to, NO in the
pulmonary arteries. Following exposure of piglets to
chronic hypobaric hypoxia from birth, isolated pulmonary arteries failed to establish normal endothelium-dependent relaxation by three days of age
[133] and the newly established response was significantly attenuated in animals exposed to hypoxia from
three days of life onwards. NOS protein was still relatively abundant but it decreased and the activity of
Pharmacological Reports, 2006, 57, suppl., 153–164
157
calcium-dependent and independent eNOS failed to
increase after birth in animals kept hypoxic from birth
[8, 55]. Chronic hypoxia impairs endothelial Ca2+
metabolism and normal coupling between eNOS and
caveolin-1 resulting in eNOS inactivity [98]. In fetal
lambs made pulmonary hypertensive by intrauterine
ligation of the ductus arteriosus, NOS gene expression, protein and activity decreased [15]. PPHN appears to be multifactorial. It may be related to the inappropriate postnatal persistence of an endogenous
NO inhibitor such as ADMA. The circulating level of
ADMA is increased in patients with pre-eclamptic
toxaemia and the babies of these mothers are predisposed to PPHN. Importantly, abnormally high levels
of ADMA have been detected in the urine of babies
with PPHN [106]. Arginine deficiency, absolute or
relative, is a feature of the human infant with PPHN
[140] and an L-arginine infusion can be associated
with an improvement in oxygenation [113]. Newborn
lambs made pulmonary hypertensive by surgically increasing pulmonary blood flow showed impairment
of endothelium-dependent relaxation associated with
reduced circulatory levels of L-arginine [111]. Pretreatment with L-arginine attenuated pulmonary hypertensive caused by exposure to hypoxia or infusion
of the thromboxane analogue U46619 [38].
Endothelin: The circulating endothelin level remains high in experimental models of hypoxiainduced PPHN. ET-1 receptor-binding density (primarily ETA) is increased and the transient expression
of ETB receptors does not occur [101]. Isolated porcine pulmonary arteries from chronically hypoxic piglets showed a 2–3 fold increase in the contractile response to ET-1, a lack of vasodilator ETB response at
3 days as indicated by the absence of response to the
ETB antagonist BQ788 and co-constriction of adjacent isolated bronchi [116, 117]. Co-constriction of
pulmonary arteries and bronchi is a well-recognised
clinical feature of infants with pulmonary hypertension. Preproendothelin mRNA was significantly elevated in fetal ovine lung tissue after ductal ligation in
utero and ETA expression was elevated [15].
Prostacyclin: The release of PGI2 is reduced in
many forms of pulmonary arterial hypertension in
man and is assumed to be low in newborns with
PPHN. The administration of PGI2 alleviates hypoxic
pulmonary vasoconstriction in newborn infants and
animals with PPHN.
Activation of Rho GTPases: Rho GTPases are
key regulators of endothelial actin dynamics, thereby
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influencing both vascular reactivity and endothelial
permeability [128, 135, 136, 143]. Activation of
RhoA has been associated with the development of
pulmonary hypertension [11, 34, 86, 115] possibly by
mediating the effects of vasoconstrictors such as angiotensin II [34, 121, 145], ET-1 and acetylcholine [87, 96,
115] and downregulating eNOS expression and NO
production in endothelial cells [32, 72, 91, 131].
Treatment of PPHN
In sustained pulmonary hypertension treatment in the
neonatal period focuses primarily on increasing vasodilatation. The rationale for giving NO and possibly
a phosphodiesterase inhibitor such as sildenafil, is
that there is an absolute or relative lack of the endogenous substance. This form of pulmonary hypertension
is the most amenable to experimental study. The overexpression of vasodilator genes such as eNOS,
prepro-calcitonin gene-related peptide and PGI synthase have produced promising results in animal models of PPHN [67]. In systemic hypertension overexpression of the vasodilator genes atrial natriuretic
peptide [77], kallikrein, adrenomedullin [26] and
eNOS [78] via transfer of naked DNA or viral delivery systems had a blood pressure lowering effect in
rat models. Conversely, inhibition of vasoconstrictors
such as angiotensin receptor antagonists or intracardiac injections of viral particles containing antisense
nucleotides to angiotensin or the angiotensin II type I
receptor into the adult spontaneously hypertensive rat
produced a sustained systemic blood pressurelowering effect combined with a reversal of endothelial dysfunction [65].
Statins might be helpful in the treatment of PPHN.
Statins inhibit the prenylation of Rho proteins and
their translocation to the membrane inhibiting their
activity [120]. As statins have anti-leakage and antiinflammatory effects and increase NO production by
endothelial cells [83, 84] they could be useful in disorders like PPHN characterised by endothelial dysfunction. Inhibition of Rho kinase is another therapeutic possibility. Giving the Rho kinase inhibitor
fasudil to nursing fawn-hooded rats and their newborn
offspring kept in mild hypoxic conditions ameliorated
pulmonary hypertension in the newborns [86].
Many of the agonists which influence relaxation
and contraction also influence SMCs proliferation,
and certain growth factors can act as contractile agonists. In theory, therapeutic regimes aimed at maxi-
The pulmonary endothelium in the perinatal period
Sheila G. Haworth
mising relaxation using long-term NO donors or supplementation with L-arginine might also modify
structural remodelling, as PGI2 treatment is thought to
do in primary pulmonary hypertension. Clinically we
also focus on reducing contraction by using ET-1 receptor antagonists. These agents attenuate the pulmonary hypertensive response to experimental hypoxia
[103], and ET-1 has both a vasoconstrictor and mitogenic effect. Ultimately, our aim must be to control
excessive reactivity and structural remodelling using
therapeutic agents, which exploit the interactions between the signalling pathways controlling these
events.
Conclusions
The pulmonary endothelium plays a crucial role in the
regulation of pulmonary vascular tone and structural
remodelling in perinatal life. Improving the management of babies with PPHN requires further extensive
study of the signal transduction mechanisms regulating endothelial function during this most critical period of life.
References:
1. Abman SH, Chatfield BA, Hall SL, McMurtry IF: Role
of endothelium-derived relaxing factor during transition
of pulmonary circulation at birth. Am J Physiol, 1990,
259, H1921–1927.
2. Abman SH, Chatfield BA, Rodman DM, Hall SL,
McMurtry IF: Maturational changes in endotheliumderived relaxing factor activity of ovine pulmonary arteries in vitro. Am J Physiol, 1991, 260, L280–285.
3. Abman SH, Stenmark KR: Changes in lung eicosanoid
content during normal and abnormal transition in perinatal lambs. Am J Physiol, 1992, 262, L214–222.
4. Accurso FJ, Alpert B, Wilkening RB, Petersen RG,
Meschia G: Time-dependent response of fetal pulmonary
blood flow to an increase in fetal oxygen tension. Respir
Physiol, 1986, 63, 43–52.
5. Aherne W, Dawkins MJ: The removal of fluid from the
pulmonary airways after birth in the rabbit, and the effect
on this of prematurity and pre-natal hypoxia. Biol Neonat, 1964, 78, 214–229.
6. Alshihabi SN, Chang YS, Frangos JA, Tarbell JM: Shear
stress-induced release of PGE2 and PGI2 by vascular
smooth muscle cells. Biochem Biophys Res Commun,
1996, 224, 808–814.
7. Arai K, Yanaihara T: Steroid hormone changes in fetal
blood during labor. Am J Obstet Gynecol, 1977, 127,
879–883.
8. Arrigoni FI, Hislop AA, Haworth SG, Mitchell JA: Newborn intrapulmonary veins are more reactive than arteries
in normal and hypertensive piglets. Am J Physiol, 1999,
277, L887–892.
9. Arrigoni FI, Hislop AA, Pollock JS, Haworth SG,
Mitchell JA: Birth upregulates nitric oxide synthase activity in the porcine lung. Life Sci, 2002, 70, 1609–1620.
10. Arrigoni FI, Vallance P, Haworth SG, Leiper JM: Metabolism of asymmetric dimethylarginines is regulated in
the lung developmentally and with pulmonary hypertension induced by hypobaric hypoxia. Circulation, 2003,
107, 1195–1201.
11. Bailly K, Ridley AJ, Hall SM, Haworth SG: RhoA activation by hypoxia in pulmonary arterial smooth muscle
cells is age and site specific. Circ Res, 2004, 94, 1383–1391.
12. Baluk P, Thurston G, Murphy TJ, Bunnett NW, McDonald DM: Neurogenic plasma leakage in mouse airways.
Br J Pharmacol, 1999, 126, 522–528.
13. Benthin G, Cederqvist T, Ciabattoni G, Kjellmer I,
Wennmalm A: Paired analysis of thromboxane and prostacyclin metabolites in urine from healthy mothers and
their children. Prostaglandins, 1990, 40, 81–88.
14. Bhat GB, Block ER: Hypoxia directly increases serotonin transport by porcine pulmonary artery endothelial
cell plasma membrane vesicles. Am J Respir Cell Mol
Biol, 1990, 3, 363–367.
15. Black SM, Johengen MJ, Soifer SJ: Coordinated regulation of genes of the nitric oxide and endothelin pathways
during the development of pulmonary hypertension in fetal lambs. Pediatr Res, 1998, 44, 821–830.
16. Bland RD, McMillan DD, Bressack MA, Dong L: Clearance of liquid from lungs of newborn rabbits. J Appl
Physiol, 1980, 49, 171–177.
17. Bloomfield GL, Holloway S, Ridings PC, Fisher BJ,
Blocher CR, Sholley M, Bunch T et al.: Pretreatment
with inhaled nitric oxide inhibits neutrophil migration
and oxidative activity resulting in attenuated sepsis-induced
acute lung injury. Crit Care Med, 1997, 25, 584–593.
18. Boels PJ, Deutsch J, Gao B, Haworth SG: Maturation of
the response to bradykinin in resistance and conduit pulmonary arteries. Cardiovasc Res, 1999, 44, 416–428.
19. Boels PJ, Deutsch J, Gao B, Haworth SG: Perinatal development influences mechanisms of bradykinin-induced
relaxations in pulmonary resistance and conduit arteries
differently. Cardiovasc Res, 2001, 51, 140–150.
20. Brannon TS, North AJ, Wells LB, Shaul PW: Prostacyclin synthesis in ovine pulmonary artery is developmentally regulated by changes in cyclooxygenase-1 gene expression. J Clin Invest, 1994, 93, 2230–2235.
21. Buga GM, Gold ME, Fukuto JM, Ignarro LJ: Shear
stress-induced release of nitric oxide from endothelial
cells grown on beads. Hypertension, 1991, 17, 187–193.
22. Cassin S, Kristova V, Davis T, Kadowitz P, Gause G:
Tone-dependent responses to endothelin in the isolated
perfused fetal sheep pulmonary circulation in situ. J Appl
Physiol, 1991, 70, 1228–1234.
Pharmacological Reports, 2006, 57, suppl., 153–164
159
23. Cassin S, Leffler CW, Tyler TL: Prostaglandins and
regulation of the pulmonary circulation in the perinatal
period. Ann Rech, 1977, Vet 8, 396–404.
24. Cassin S, Tod ML, Frisinger JE, Jordan JA, Philips JB:
Use of prostacyclin in persistent fetal circulation. Lancet,
1979, 2, 638.
25. Cassin S, Winikor I, Tod M, Philips J, Frisinger J, Jordan
J, Gibbs C: Effects of prostacyclin on the fetal pulmonary circulation. Pediatr Pharmacol (New York), 1981, 1,
197–207.
26. Chao J, Kato K, Zhang JJ, Dobrzynski E, Wang C, Agata
J, Chao L: Human adrenomedullin gene delivery protects
against cardiovascular remodeling and renal injury. Peptides, 2001, 22, 1731–1737.
27. Chiu YJ, Kusano K, Thomas TN Fujiwara K: Endothelial cell-cell adhesion and mechanosignal transduction.
Endothelium, 2004, 11, 59–73.
28. Dawes GS: Pulmonary circulation in the foetus and
new-born. Br Med Bull, 1966, 22, 61–65.
29. DeFouw DO: Structural heterogeneity within the pulmonary microcirculation of the normal rat. Anat Rec, 1988,
221, 645–654.
30. Eibl G, Forgacs B, Hotz HG, Buhr HJ, Foitzik T: Endothelin A but not endothelin B receptor blockade reduces
capillary permeability in severe experimental pancreatitis. Pancreas, 2002, 25, e15–20.
31. Ellsworth ML, Gregory TJ, Newell JC: Pulmonary prostacyclin production with increased flow and sympathetic
stimulation. J Appl Physiol, 1983, 55, 1225–1231.
32. Eto M, Barandier C, Rathgeb L, Kozai T, Joch H, Yang
Z, Luscher TF: Thrombin suppresses endothelial nitric
oxide synthase and upregulates endothelin-converting
enzyme-1 expression by distinct pathways: role of
Rho/ROCK and mitogen-activated protein kinase. Circ
Res, 2001, 89, 583–590.
33. Evans AM, Osipenko ON, Haworth SG, Gurney AM:
Resting potentials and potassium currents during development of pulmonary artery smooth muscle cells. Am
J Physiol, 1998, 275, H887–899.
34. Fagan KA, Oka M, Bauer NR, Gebb SA, Ivy DD, Morris
KG, McMurtry IF: Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase. Am J Physiol
Lung Cell Mol Physiol, 2004, 287, L656–664.
35. Feng D, Nagy JA, Pyne K, Hammel I, Dvorak HF, Dvorak AM: Pathways of macromolecular extravasation
across microvascular endothelium in response to VPF/VEGF
and other vasoactive mediators. Microcirculation, 1999,
6, 23–44.
36. Feng Y, Venema VJ, Venema RC, Tsai N, Behzadian
MA, Caldwell RB: VEGF-induced permeability increase
is mediated by caveolae. Invest Ophthalmol Vis Sci,
1999, 40, 157–167.
37. Fineman JR, Chang R, Soifer SJ: L-Arginine, a precursor
of EDRF in vitro, produces pulmonary vasodilation in
lambs. Am J Physiol, 1991, 261, H1563–1569.
38. Fineman JR, Chang R, Soifer SJ: EDRF inhibition augments pulmonary hypertension in intact newborn lambs.
Am J Physiol, 1992, 262, H1365–1371.
39. Fukuroda T, Nishikibe M, Ohta Y, Ihara M, Yano M,
Ishikawa K, Fukami T, Ikemoto F: Analysis of responses
160
Pharmacological Reports, 2006, 57, suppl., 153–164
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
to endothelins in isolated porcine blood vessels by using
a novel endothelin antagonist, BQ-153. Life Sci, 1992,
50, PL107–112.
Gamble JR, Drew J, Trezise L, Underwood A, Parsons
M, Kasminkas L, Rudge J et al.: Angiopoietin-1 is an antipermeability and anti-inflammatory agent in vitro and
targets cell junctions. Circ Res, 2000, 87, 603–607.
Gao Y, Zhou H, Raj JU: Endothelium-derived nitric oxide plays a larger role in pulmonary veins than in arteries
of newborn lambs. Circ Res, 1995, 76, 559–565.
Garat C, Meignan M, Matthay MA, Luo DF, Jayr C: Alveolar epithelial fluid clearance mechanisms are intact
after moderate hyperoxic lung injury in rats. Chest, 1997,
111, 1381–1388.
Garcia JG, Liu F, Verin AD, Birukova A, Dechert MA,
Gerthoffer WT, Bamberg JR, English D: Sphingosine
1-phosphate promotes endothelial cell barrier integrity
by Edg-dependent cytoskeletal rearrangement. J Clin Invest, 2001, 108, 689–701.
Gebb S, Stevens T: On lung endothelial cell heterogeneity. Microvasc Res, 2004, 68, 1–12.
Geisterfer AA, Peach MJ, Owens GK: Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic
smooth muscle cells. Circ Res, 1988, 62, 749–756.
Gelly C, Sumida C, Gulino, Pasqualini JR: Concentrations of oestradiol and oestrone in plasma, uterus and
other tissues of fetal guinea-pigs: their relationship to uptake and specific binding of [3H]oestradiol. J Endocrinol, 1981, 89, 71–77.
Govers R, Rabelink TJ: Cellular regulation of endothelial nitric oxide synthase. Am J Physiol Renal Physiol,
2001, 280, F193–206.
Greenberg JM, Thompson FY, Brooks SK, Shannon JM,
McCormick-Shannon K, Cameron JE et al.: Mesenchymal expression of vascular endothelial growth factors D
and A defines vascular patterning in developing lung.
Dev Dyn, 2002, 224, 144–153.
Hall SM, Haworth SG: Normal adaptation of pulmonary
arterial intima to extrauterine life in the pig: ultrastructural studies. J Pathol, 1986, 149, 55–66.
Hata AN, Breyer RM: Pharmacology and signaling of
prostaglandin receptors: multiple roles in inflammation
and immune modulation. Pharmacol Ther, 2004, 103,
147–166.
Haworth SG: Pulmonary hypertension in childhood. Eur
Respir, 1993, J 6, 1037–1043.
Haworth SG, Hall SM, Chew M, Allen K: Thinning of
fetal pulmonary arterial wall and postnatal remodelling:
ultrastructural studies on the respiratory unit arteries of
the pig. Virchows Arch A Pathol Anat Histopathol, 1987,
411, 161–171.
Hislop AA, Mak JC, Reader JA, Barnes PJ, Haworth SG:
Muscarinic receptor subtypes in the porcine lung during postnatal development. Eur J Pharmacol, 1998, 359, 211–221.
Hislop AA, Springall DR, Buttery LD, Pollock JS, Haworth SG: Abundance of endothelial nitric oxide synthase in newborn intrapulmonary arteries. Arch Dis
Child Fetal Neonatal Ed, 1995, 73, F17–21.
Hislop AA, Springall DR, Oliveira H,Pollock JS, Polak
J, Haworth SG: Endothelial nitric oxide synthase in hy-
The pulmonary endothelium in the perinatal period
Sheila G. Haworth
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
poxic newborn porcine pulmonary vessels Arch Dis
Child Fetal Neonatal Ed, 1997, 77, F16–22.
Hislop AA, Zhao YD, Springall DR, Polak JM, Haworth
SG: Postnatal changes in endothelin-1 binding in porcine
pulmonary vessels and airways. Am J Respir Cell Mol
Biol, 1995, 12, 557–566.
Hong HJ, Chan P, Liu JC, Juan SH, Huang MT, Lin JG,
Cheng TH: Angiotensin II induces endothelin-1 gene expression via extracellular signal-regulated kinase pathway in rat aortic smooth muscle cells. Cardiovasc Res,
2004, 61, 159–168.
Ihara M, Saeki T, Funabashi K, Nakamichi K, Yano M,
Fukuroda T, Miyaji M et al.: Two endothelin receptor
subtypes in porcine arteries. J Cardiovasc Pharmacol,
1991, 17, Suppl 7, S119–121.
Ilan N, Madri JA: PECAM-1: old friend, new partners.
Curr Opin Cell Biol, 2003, 15, 515–524.
Ivy DD, le Cras TD, Parker TA, Zenge JP, Jakkula M,
Markham NE, Kinsella JP, Abman SH: Developmental
changes in endothelin expression and activity in the
ovine fetal lung. Am J Physiol Lung Cell Mol Physiol,
2000, 278, L785–793.
Ivy DD, Kinsella JP, Abman SH: Physiologic characterization of endothelin A and B receptor activity in the
ovine fetal pulmonary circulation. J Clin Invest, 1994,
93, 2141–2148.
Jun SS, Chen Z, Pace MC, Shaul PW: Estrogen upregulates cyclooxygenase-1 gene expression in ovine fetal
pulmonary artery endothelium. J Clin Invest, 1998,102,
176–183.
Jun SS, Chen Z, Pace MC, Shaul PW: Glucocorticoids
downregulate cyclooxygenase-1 gene expression and
prostacyclin synthesis in fetal pulmonary artery endothelium. Circ Res, 1999, 84, 193–200.
Kaapa P, Seppanen M, Kero P, Saraste M: Pulmonary hemodynamics after synthetic surfactant replacement in
neonatal respiratory distress syndrome. J Pediatr, 1993,
123, 115–119.
Katovich MJ, Gelband CH, Reaves P, Wang HW, Raizada MK: Reversal of hypertension by angiotensin II
type 1 receptor antisense gene therapy in the adult SHR.
Am J Physiol, 1999, 277, H1260–1264.
Kawai N, Bloch DB, Filippov G, Rabkina D, Suen HC,
Losty PD, Janssens SP et al.: Constitutive endothelial nitric oxide synthase gene expression is regulated during
lung development. Am J Physiol, 1995, 268, L589–595.
Khurana R, Martin JF, Zachary I: Gene therapy for cardiovascular disease: a case for cautious optimism. Hypertension, 2001, 38, 1210–1216.
Kobzik L, Bredt DS, Lowenstein CJ, Drazen J, Gaston
B, Sugarbaker D, Stamler JS: Nitric oxide synthase in
human and rat lung: immunocytochemical and histochemical localization. Am J Respir Cell Mol Biol, 1993,
9, 371–377.
Kogo H, Aiba T, Fujimoto T: Cell type-specific occurrence of caveolin-1alpha and -1beta in the lung caused
by expression of distinct mRNAs. J Biol Chem, 2004,
279, 25574–25581.
Kuhl PG, Cotton RB, Schweer H, Seyberth HW: Endogenous formation of prostanoids in neonates with per-
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
sistent pulmonary hypertension. Arch Dis Child, 1989,
64, 949–952.
Lakshminrusimha S, Steinhorn RH: Pulmonary vascular
biology during neonatal transition. Clin Perinatol, 1999,
26, 601–619.
Laufs U, Liao JK: Targeting Rho in cardiovascular disease. Circ Res, 2000, 87, 526–528.
Leffler CW, Hessler JR, Green RS: The onset of breathing at birth stimulates pulmonary vascular prostacyclin
synthesis. Pediatr Res, 1984, 18, 938–942.
Levy M, Souil E, Sabry S, Favatier F, Vaugelade P, Mercier JC, Dall’Ava-Santucci J, Dinh-Xuan AT: Maturational changes of endothelial vasoactive factors and pulmonary vascular tone at birth. Eur Respir J, 2000, 15,
158–165.
Li RC, Cindrova-Davies T, Skepper JN, Sellers LA:
Prostacyclin induces apoptosis of vascular smooth muscle cells by a cAMP-mediated inhibition of extracellular
signal-regulated kinase activity and can counteract the
mitogenic activity of endothelin-1 or basic fibroblast
growth factor. Circ Res, 2004, 94, 759–767.
Lim H, Dey SK: A novel pathway of prostacyclin
signaling-hanging out with nuclear receptors. Endocrinology, 2002, 143, 3207–3210.
Lin KF: Human atrial natruiretic peptide gene delivery
reduces blood pressure in hypertensive rats. Hypertension, 2001, 38, E37–47.
Lin KF, Chao L, Chao J: Prolonged reduction of high
blood pressure with human nitric oxide synthase gene
delivery. Hypertension, 1997, 30, 307–313.
Liu SF, Hislop AA, Haworth SG, Barnes PJ: Developmental changes in endothelium-dependent pulmonary
vasodilatation in pigs. Br J Pharmacol, 1992, 106, 324–330.
MacAllister RJ, Parry H, Kimoto M, Ogawa T, Russell
RJ, Hodson H, Whitley GS, Vallance P: Regulation of
nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br J Pharmacol, 1996, 119, 1533–1540.
Maguire JJ, Davenport AP: Endothelin receptor expression and pharmacology in human saphenous vein graft.
Br J Pharmacol, 1999, 126, 443–450.
Marszalek A, Daa T, Kashima K, Nakayama I, Yokoyama
S: Ultrastructural and morphometric studies related to
expression of the cell adhesion molecule
PECAM-1/CD31 in developing rat lung. J Histochem
Cytochem, 2000, 48, 1283–1289.
Mason JC: Statins and their role in vascular protection.
Clin Sci (Lond), 2003, 105, 251–266.
Mason JC: The statins – therapeutic diversity in renal
disease? Curr Opin Nephrol Hypertens, 2005, 14, 17–24.
Matsumoto N, Manabe H, Ochiai J, Fujita N, Takagi T,
Uemura M, Naito Y et al.: An AT1-receptor antagonist
and an angiotensin-converting enzyme inhibitor protect
against hypoxia-induced apoptosis in human aortic endothelial cells through upregulation of endothelial cell nitric oxide synthase activity. Shock, 2003, 19, 547–552.
McMurtry IF, Bauer NR, Fagan KA, Nagaoka T, Gebb
SA, Oka M: Hypoxia and Rho/Rho-kinase signaling.
Lung development versus hypoxic pulmonary hypertension. Adv Exp Med Biol, 2003, 543, 127–137.
Miao L, Dai Y, Zhang JL: Mechanism of RhoA/Rho kinase activation in endothelin-1-induced contraction in
Pharmacological Reports, 2006, 57, suppl., 153–164
161
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
162
rabbit basilar artery. Am J Physiol Heart Circ Physiol,
2002, 283, H983–989.
Miller AA, Hislop AA, Stidwell R, Vallance PJ, Haworth
SG: Postnatal adaptation of pulmonary arteries is gender
dependent in endothelial nitric oxide synthase deficient
mice. Am J Resp Crit Care Med, 2003, 167, A823.
Miller AA, Hislop AA, Vallance PJ, Haworth SG: Deletion of the e NOS gene has a greater impact on the pulmonary circulation of male than female mice. Am
J Physiol Lung Cell Mol Physiol, 2005, 289, L299–306.
Mills AN, Haworth SG: Greater permeability of the neonatal lung. Postnatal changes in surface charge and biochemistry of porcine pulmonary capillary endothelium.
J Thorac Cardiovasc Surg, 1991, 101, 909–916.
Ming XF, Viswambharan H, Barandier C, Ruffieux J,
Kaibuchi K, Rusconi S, Yang Z: Rho GTPase/Rho kinase negatively regulates endothelial nitric oxide synthase phosphorylation through the inhibition of protein
kinase B/Akt in human endothelial cells. Mol Cell Biol,
2002, 22, 8467–8477.
Minshall RD, Sessa WC, Stan RV, Anderson RG, Malik
AB: Caveolin regulation of endothelial function. Am
J Physiol Lung Cell Mol Physiol, 2003, 285, L1179–1183.
Moncada S, Vane JR: The role of prostacyclin in vascular tissue. Fed Proc, 1979, 38, 66–71.
Moreau P, d’Uscio LV, Shaw S, Takase H, Barton M,
Luscher TF: Angiotensin II increases tissue endothelin
and induces vascular hypertrophy: reversal by ET(A)receptor antagonist. Circulation, 1997, 96, 1593–1597.
Moreno L, Losada B, Cogolludo A, Lodi F, Lugnier C,
Villamor E, Moro M et al.: Postnatal maturation of phosphodiesterase 5 (PDE5) in piglet pulmonary arteries: activity, expression, effects of PDE5 inhibitors, and role of
the nitric oxide/cyclic GMP pathway. Pediatr Res, 2004,
56, 563–570.
Mori M, Tsushima H: Activation of Rho signaling contributes to lysophosphatidic acid-induced contraction of
intact ileal smooth muscle of guinea-pig. Can J Physiol
Pharmacol, 2000, 78, 729–736.
Morrell NW, Grieshaber SS, Danilov SM, Majack RA,
Stenmark KR: Developmental regulation of angiotensin
converting enzyme and angiotensin type 1 receptor in the
rat pulmonary circulation. Am J Respir Cell Mol Biol,
1996, 14, 526–537.
Murata T, Sato K, Hori M, Ozaki H, Karaki H: Decreased
endothelial nitric-oxide synthase (eNOS) activity resulting from abnormal interaction between eNOS and its
regulatory proteins in hypoxia-induced pulmonary hypertension. J Biol Chem, 2002, 277, 44085–44092.
Nakagawa O, Tanaka I, Usui T, Harada M, Sasaki Y, Itoh
H, Yoshimasa T et al.: Molecular cloning of human prostacyclin receptor cDNA and its gene expression in the
cardiovascular system. Circulation, 1994, 90, 1643–1647.
Nandi M, Leiper J, Arrigoni F, Hislop A, Vallance P, Haworth SG: Developmental regulation of GTP-CH1 in the
porcine lung and its relationship to pulmonary vascular
relaxation. Pediatr Res, 2006, 59, 767–772.
Noguchi Y, Hislop AA, Haworth SG: Influence of hypoxia on endothelin-1 binding sites in neonatal porcine
pulmonary vasculature. Am J Physiol, 1997, 272, H669–678.
Pharmacological Reports, 2006, 57, suppl., 153–164
102. Olver RE, Walters DV, Wilson SM: Developmental regulation of lung liquid transport. Annu Rev Physiol, 2004,
66, 77–101.
103. Oparil S, Chen SJ, Meng QC, Elton TS, Yano M, Chen
YF: Endothelin-A receptor antagonist prevents acute
hypoxia-induced pulmonary hypertension in the rat. Am
J Physiol, 1995, 268, L95–100.
104. Parker TA, le Cras TD, Kinsella JP, Abman SH: Developmental changes in endothelial nitric oxide synthase expression and activity in ovine fetal lung. Am J Physiol
Lung Cell Mol Physiol, 2000, 278, L202–208.
105. Philips JB: Prostaglandins and related compounds in the
perinatal pulmonary circulation. Pediatr Pharmacol (New
York), 1984, 4, 129–142.
106. Pierce CM, Krywawych S, Petros AJ: Assymetric dimethyl arginine and symmetric dimethyl arginine levels
in infants with persistent pulmonary hypertension of the
newborn. Pediatr Crit Care Med, 2004, 5, 517–520.
107. Polglase GR, Wallace MJ, Grant DA, Hooper SB: Influence of fetal breathing movements on pulmonary hemodynamics in fetal sheep. Pediatr Res, 2004, 56, 932–938.
108. Porter LP, McNamee JE, Wolf MB: Endothelin-1 induces
endothelial barrier failure in the cat hindlimb. Shock,
1999, 11, 111–114.
109. Ramirez MI, Pollack L, Millien G, Cao YX, Hinds A,
Williams MC: The alpha-isoform of caveolin-1 is
a marker of vasculogenesis in early lung development.
J Histochem Cytochem, 2002, 50, 33–42.
110. Rawlings NC, Ward WR: Correlations of maternal and fetal endocrine events with uterine pressure changes around
parturition in the ewe. J Reprod Fertil, 1978, 54, 1–8.
111. Reddy VM, Wong J, Liddicoat JR, Johengen M, Chang
R, Fineman JR: Altered endothelium-dependent responses in lambs with pulmonary hypertension and increased pulmonary blood flow. Am J Physiol, 1996, 271,
H562–570.
112. Resta TC, Gonzales RJ, Dail WG, Sanders TC, Walker
BR: Selective upregulation of arterial endothelial nitric
oxide synthase in pulmonary hypertension. Am J Physiol,
1997, 272, H806–813.
113. Saidy K, al-Alaiyan S: The use of L-arginine [correction
of F-arginine] and phosphodiesterase inhibitor (dipyridamole) to wean from inhaled nitric oxide. Indian J Pediatr,
2001, 68, 175–177.
114. Sanchez LS, de la Monte SM, Filippov G, Jones RC, Zapol WM, Bloch KD: Cyclic-GMP-binding, cyclic-GMPspecific phosphodiesterase (PDE5) gene expression is
regulated during rat pulmonary development. Pediatr
Res, 1998, 43,163–168.
115. Sauzeau V, Rolli-Derkinderen M, Lehoux S, Loirand G,
Pacaud P: Sildenafil prevents change in RhoA expression
induced by chronic hypoxia in rat pulmonary artery. Circ
Res, 2003, 93, 630–637.
116. Schindler MB, Hatch D, Hislop AA, Haworth SG: Enhanced constriction of bronchi and pulmonary arteries to
endothelin in pulmonary hypertension. Circulation,
1997, 96, Suppl 1, 427.
117. Schindler MB, Hislop AA, Haworth SG: Porcine pulmonary artery and bronchial responses to endothelin-1 and
norepinephrine on recovery from hypoxic pulmonary hypertension. Pediatr Res, 2006, 60, 71–76.
The pulmonary endothelium in the perinatal period
Sheila G. Haworth
118. Schubert W, Frank PG, Woodman SE, Hyogo H, Cohen
DE, Chow CW, Lisanti MP: Microvascular hyperpermeability in caveolin-1 (–/–) knock-out mice. Treatment
with a specific nitric-oxide synthase inhibitor, L-name,
restores normal microvascular permeability in Cav-1 null
mice. J Biol Chem, 2002, 277, 40091–40098.
119. Schutte H, Mayer K, Burger H, Witzenrath M, Gessler T,
Seeger W, Grimminger F: Endogenous nitric oxide synthesis and vascular leakage in ischemic-reperfused rabbit
lungs. Am J Respir Crit Care Med, 2001, 164, 412–418.
120. Seasholtz TM. Brown JH: Rho signalling in vascular diseases. Mol Interv, 2004, 4, 348–357.
121. Seko T, Ito M, Kureishi Y, Okamoto R, Moriki N, Onishi
K, Isaka N et al.: Activation of RhoA and inhibition of
myosin phosphatase as important components in hypertension in vascular smooth muscle. Circ Res, 2003, 92,
411–418.
122. Shaul PW, Afshar S, Gibson LL, Sherman TS, Kerecman
JD, Grubb PH, Yoder BA, McCurnin DC: Developmental changes in nitric oxide synthase isoform expression
and nitric oxide production in fetal baboon lung. Am
J Physiol Lung Cell Mol Physiol, 2002, 283, L1192–1199.
123. Shaul PW, Farrar MA, Magness RR: Oxygen modulation
of pulmonary arterial prostacyclin synthesis is developmentally regulated. Am J Physiol, 1993, 265, H621–628.
124. Shaul PW, Pace MC, Chen Z, Brannon TS: Developmental changes in prostacyclin synthesis are conserved in
cultured pulmonary endothelium and vascular smooth
muscle. Am J Respir Cell Mol Biol, 1999, 20, 113–121.
125. Sherman TS, Chambliss KL, Gibson LL, Pace MC,
Mendelsohn ME, Pfister SL, Shaul PW: Estrogen acutely
activates prostacyclin synthesis in ovine fetal pulmonary
artery endothelium. Am J Respir Cell Mol Biol, 2002,
26, 610–616.
126. Soifer SJ, Loitz RD, Roman C, Heymann MA: Leukotriene end organ antagonists increase pulmonary blood
flow in fetal lambs. Am J Physiol, 1985, 249, H570–576.
127. Solowiej A, Biswas P, Graesser D, Madri JA: Lack of
platelet endothelial cell adhesion molecule-1 attenuates
foreign body inflammation because of decreased angiogenesis. Am J Pathol, 2003, 162, 953–962.
128. Sorokina EM, Chernoff J: Rho-GTPases: New members,
new pathways. J Cell Biochem, 2005, 94, 225–231.
129. Stenmark KR, James SL, Voelkel NF, Toews WH,
Reeves JT, Murphy RC: Leukotriene C4 and D4 in neonates with hypoxemia and pulmonary hypertension.
N Engl J Med, 1983, 309, 77–80.
130. Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J: Inflammation and angiotensin II. Int
J Biochem Cell Biol, 2003, 35, 881–900.
131. Takemoto M, Sun J, Hiroki J, Shimokawa H, Liao JK:
Rho-kinase mediates hypoxia-induced downregulation of
endothelial nitric oxide synthase. Circulation, 2002, 106,
57–62.
132. Topper JN, Cai J, Falb D, Gimbrone MA Jr.: Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric
oxide synthase are selectively up-regulated by steady
laminar shear stress. Proc Natl Acad Sci USA, 1996, 93,
10417–10422.
133. Tulloh RM, Hislop AA, Boels PJ, Deutsch J, Haworth
SG: Chronic hypoxia inhibits postnatal maturation of
porcine intrapulmonary artery relaxation. Am J Physiol,
1997, 272, H2436–2445.
134. Vallance P, Leiper J: Cardiovascular biology of the
asymmetric dimethylarginine: dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc
Biol, 2004, 24, 1023–1030.
135. van Nieuw Amerongen GP, van Hinsbergh VW: Cytoskeletal effects of rho-like small guanine nucleotidebinding proteins in the vascular system. Arterioscler
Thromb Vasc Biol, 2001, 21, 300–311.
136. van Nieuw Amerongen GP, van Hinsbergh VW: Targets
for pharmacological intervention of endothelial hyperpermeability and barrier function. Vasc Pharmacol, 2002,
39, 257–272.
137. Vane JR, Botting RM: Pharmacodynamic profile of prostacyclin. Am J Cardiol, 1995, 75, 3A–10A.
138. Vane J, Corin RE: Prostacyclin: a vascular mediator. Eur
J Vasc Endovasc Surg, 2003, 26, 571–578.
139. Velvis H, Moore P, Heymann MA: Prostaglandin inhibition prevents the fall in pulmonary vascular resistance as
a result of rhythmic distension of the lungs in fetal
lambs. Pediatr Res, 1991, 30, 62–68.
140. Vosatka RJ, Kashyap S, Trifiletti RR: Arginine deficiency
accompanies persistent pulmonary hypertension of the
newborn. Biol Neonate, 1994, 66, 65–70.
141. Wallace KB, Bailie MD, Hook JB: Development of
angiotensin-converting enzyme in fetal rat lungs. Am
J Physiol, 1979. 236, R57–60.
142. Wharton J, Davie N, Upton PD, Yacoub MH, Polak JM,
Morrell NW: Prostacyclin analogues differentially inhibit
growth of distal and proximal human pulmonary artery
smooth muscle cells. Circulation, 2000, 102, 3130–3136.
143. Wojciak-Stothard B, Tsang LY, Haworth SG: Rac and
Rho play opposing roles in the regulation of hypoxia/
reoxygenation-induced permeability changes in pulmonary artery endothelial cells. Am J Physiol Lung Cell
Mol Physiol, 2004.
144. Wojciak-Stothard B, Tsang LY, Paleolog E, Hakk SM,
Haworth SG: Rac1 and Rho A as regulators of endothelial phenotype and barrier function in hypoxia-induced
neonatal pulmonary hypertension Am J Physiol Lung
Cell Mol Physiol, 2006, 290, L1173–1182.
145. Yamakawa T, Tanaka S, Numaguchi K, Yamakawa Y,
Motley ED, Ichihara S, Inagami T: Involvement of Rhokinase in angiotensin II-induced hypertrophy of rat vascular smooth muscle cells. Hypertension, 2000, 35, 313–318.
146. Yamamoto M, Shimokata K, Nagura H: An immunohistochemical study on phenotypic heterogeneity of human
pulmonary vascular endothelial cells. Virchows Arch
A Pathol Anat Histopathol, 1988, 412, 479–486.
147. Yan SF, Ogawa S, Stern DM, Pinsky DJ: Hypoxiainduced modulation of endothelial cell properties: regulation of barrier function and expression of interleukin-6.
Kidney Int, 1997, 51, 419–425.
148. Yanagisawa M, Kurihara H, Kimura S, Goto K, Masaki
T: A novel peptide vasoconstrictor, endothelin, is produced by vascular endothelium and modulates smooth muscle Ca2+ channels. J Hypertens Suppl, 1988, 6, S188–191.
Pharmacological Reports, 2006, 57, suppl., 153–164
163
149. Zenge JP, Rairigh RL, Grover TR, Storme L, Parker TA,
Kinsella JP, Abman SH: NO and prostaglandin interactions during hemodynamic stress in the fetal ovine pulmonary circulation. Am J Physiol Lung Cell Mol
Physiol, 2001, 281, L1157–1163.
150. Ziegler JW, Ivy DD, Kinsella JP, Abman SH: The role of
nitric oxide, endothelin, and prostaglandins in the transi-
164
Pharmacological Reports, 2006, 57, suppl., 153–164
tion of the pulmonary circulation. Clin Perinatol, 1995,
22, 387–403.
Received:
October 10, 2006; in revised form: November 9, 2006